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ABSTRACT

BACKGROUND AND AIMS The gastrointestinal (GI) tract extracts nutrients from ingested meals while protecting the organism from infectious agents frequently present in meals. Consequently, most animals conduct the entire digestive process within the GI tract while keeping the luminal contents entirely outside the body, separated by the tightly sealed GI epithelium. Therefore, like skin and oral cavity, the GI tract must sense luminal contents' chemical and physical properties to optimize digestion. Specialized sensory enteroendocrine cells (EECs) in GI epithelium intimately interact with luminal contents. A subpopulation of EECs expresses the mechanically gated ion channel Piezo2 and are developmentally and functionally like the skin's touch sensor: the Merkel cell. We hypothesized that Piezo2+ EECs endow the gut with intrinsic tactile sensitivity. METHODS We generated transgenic mouse models with optogenetic sensors in EECs and Piezo2 conditional knockouts. We used a range of gold-standard and novel techniques from single cells to living animals, including single-cell RNA sequencing and opto-electrophysiology, opto-organ baths with luminal shear forces, and in vivo studies that assayed GI transit while manipulating physical properties of luminal contents. RESULTS Piezo2+ EECs have transcriptomic features of synaptically connected mechanosensory epithelial cells. EEC activation by optogenetics and forces led to Piezo2-dependent alterations in colonic propagating contractions driven by intrinsic circuitry, with Piezo2+ EECs detecting small luminal forces and luminal contents' physical properties to regulate transit times in the small and large bowel. CONCLUSION The GI tract has intrinsic tactile sensitivity that depends on Piezo2+ EECs and allows it to detect luminal forces and physical properties of luminal contents to modulate physiology.

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